"A PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF OBESITY"

Abstract

STATEMENT OF INVENTION: Accordingly, the present invention relates to a pharmaceutical composition for the treatment of obesity, said composition containing fenofibrate, orlistat and pharmaceutically acceptable carrier(s), wherein the weight ratio of fenofibrate to orlistat is in the range of 12.2 : 87.8 to 62.5 : 37.5. A pharmaceutical composition containing a fibrate, orlistat and a pharmaceutically acceptable carrier, wherein the fibrate is selected from the group consisting of gemfiobrozil, fenofibrate, bezfibrate, clofibrate and ciprofibrate.

Full Text

Use of a fibrate anil orlistat for the treatment of obesity
The present invention relates to the use of a fibrate and orlistat to treat patients suffering from obesity.
I etrahydrolipslatin is an inhibitor of pancreatic lipase and is known by the generic name orlistat. The use of the. as a medicament, particularly as an nnti-ohesiu agent, and pharmaceutical compositions containing the, as an active agent are described in U.S. Patent No. 4,598.089. A process for the preparation oforlistal is described in U.S. Patent No. 4.983.746. A pharmaceutical composition comprising orlistat and sibutraminc is described in WO 99/33450.
fibrates. which arc PPAR activators, have been reported to lower plasma triglycerides and cholesterol levels and to be beneficial in the prevention of ischemic heart disease in individuals with elevated levels of LDL cholesterol. They. can also decrease to some extent elevated fibrinogen and PAI-I levels, l-ibratc compounds, e.g.. gemfibro/.il. fenofibrate, be/allbrate. and ciprofibratc. elevate the level of plasma 111)1. cholesterol.
It has now surprisingly been found that co-administration of a fibrate and orlistat results in beneficial effects in obese or overweight subjects.
Accordingly, the present invention relates to a method for the treatment of obesity, comprising co-administering an effective dose ol'a fibrate and orlistat. flic fibrate used in this method max be selected from the group consisting of gemfibro/il. lenotibrate, be/afibrate, clolibrate and ciprofibratc.
In another embodiment, the invention includes a method for the treatment of obesity, comprising co-administering an effective dose ol'a fibrate and orlistat, where the effective dose of the fibrate is in the range of about 10 to about 3000 ing per da\.
In another embodiment, the effective dose of orlislat is in the range of about 50 to about 1440 mg per day.
In another embodiment, the fibrate and orlistat are administered simultaneously, in a method lor the treatment of obesity, comprising co-administering an effective dose of a fibralc and orlistat.
In another embodiment of a method for the treatment of obesity, the fibrate and orlislat are administered sequentially.
In another embodiment, the invention includes a method for the treatment of obesity in a patient already treated with orlistat, which comprises administering to the patient an effective dose of a fibr-te. As mentioned above, the fibrate and orlistat are administered simultaneously or sequentially.
In another embodiment, the invention includes the use of a fibrate. orlistat and a pharmaceutical!) acceptable carrier in the manufacture of a medicament for the treatment of obesity. In another embodiment, the llbrate is selected from the group consisting of gemllbro/il. fenofibrate, be/allbrate, clofibrate and ciprofibrate.
As demonstrated in the present specification, the use of a llbrate and orlistat, has led to unexpectedly favourable results in that body weight control is more efficient when orlistat is co-administered with a llbrate.
furthermore, the applicant has shown that the association of both compounds allows a lower dose of orlistat to be used while maintaining the same therapeutic effects.
The invention also enables the reduction of side effects, as a lower dose of orilslat is used.
As used in this application, "co-administration" means the administration ol two or more compounds to the same patient, within a time period of up to about three to about lour hours, for example, co-administration encompasses (1) simultaneous administration of a first and second compound: (2) administration of a first compound, followed by administration of a second compound about 2 hours alter administration of the firsl compound; and (3) administration of a first compound, followed by administration of a second compound about 4 hours after administration of the llrst compound. As described herein, the present invention encompasses co-administration of a fibrate and orlistat to a patient.
In the present invention, llbrates are defined as PPARu agonists (peroxisome prolilerator activated receptor alpha agonLls), including tlbric acid derivatives (e.g. lenotlbric acid or clofibric acid) and pharmaceutically acceptable salts and esters of such tlbric acid derivatives, f'ibric acid derivatives lower the levels of Iriglyeeride-nch lipoproieins. such as VI,1)1,. raise 1IDI. levels, and have variable effects on LDL levels. The efleets on VI,1)1, levels appear to result primarily from an increase in
lipoprotein lipase activity, especially in muscle. This leads to enhanced hydrolysis of VI,1)1. triglyceride content and enhanced VLDL cataholism. Libric acid agents also may alter the composition of the VLDI,. lor example, by decreasing hepatic production ol apo( III. an inhibitor ol" lipoprotein lipase activity. These compounds arc also reported to decrease hepatic VLDI, triglyceride synthesis, possibly by inhibiting Tatty acid synthesis and by promoting laity acid oxidation.
Libratc compounds include, but are not limited to, gcinfibro/il, fenolibnUc. be/afibrate, clolibrate, ciproilbrale, and analogs, derivatives and pharmaceutical I v acceptable salts thereof.
fenofibrate is commercially available as Tricorw capsules. Lach capsule contains 67 ing of microni/.ed fenollbrate.
I enollbric acid, the active metabolite of fenollbrate. lowers plasma triglycerides apparently by inhibiting triglyceride synthesis, resulting in a reduction of VI 1)1. released into the bloodstream, and also by stimulating the cataholism of triglyceride rich lipoproleins (i.e. VLDI.).
Clolihrate is commercially available as Atromid-S* capsules. Lach capsule contains 500 mg of clotlbrate. C'Jofibrate lowers elevated serum lipids by reducing the very low-density lipoprotein fraction rich in iriglycerides. Serum cholesterol may be decreased. It may inhibit the hepatic release of lipoproteins (particularly VLDI ) and potentiate the action of lipoprotein lipase. The recommended daily dose ol clolibrale is 2 g, administered in divided doses.
(icmfihro/.il is commercially available as l.opid'H tablets. Lach tablet contains 600 mg of gemfibro/il. Gemfibro/il is a lipid regulating agent that decreases serum triglycerides and very low density lipoprotein cholesterol, and increases high density lipoprotein cholesterol. The recommended daily dose of gemllbro/il is ! 200 mg. administered in two divided doses.
I ibralcs include PPARa agonists: the PPARu agonists mav be identified according to an assay described in US Patent 6,008.2.W. Pharmaceulically acceptable salts and esters of PPARa agonists are likewise included within the scope of this invention. • Compounds which are PPARa agonists include compounds such as those described in US Patent 6,008,239. WO 97/27847. WO
07/278S7. WO 7/28H5. WO T//28I37 and WO 97/2814'). Certain tibrate compounds as described in WO 42/10468 and WO 01/80852 are also incorporated In reference herein.
According to the present invention, the preferred fibrale is fenofibrate.
Orlistat is commercially available as XcnicaKK. and is indicated in conjunction \viih a mildly hypocaloric diet for the treatment of obese patients with a both mass index (MMI) greater than or equal to 30 kg/m . or overweight patients (HMI 28 kg/in ) with associated risk factors.
( hcniically, orlistat is |2S-|2(x(R*),3(i||-N-tbrmyl-l.-leucinc l-|(3-hexyl-4~o\o-2-oxctanyl(methyl|dodecyl ester. It is also known as N-formyl-L-leucine ester with (3S.4S)-3-liexyl-4-|(2S)-2-hydroxy-tridecyl |-2-oxetanone, or (-)-letrahydrolipslatin.
According to the present invention, a preparation is defined as the formulation ol (he active compound(s) with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded b\ a carrier, which is thus in association with it. This includes tablets, powders, capsules, pills, cachets, and lo/enges which can be used as solid dose forms suitable lor oral administration.
An effective dose is defined in the present invention as the amount of a compound thai prevents or ameliorates adverse conditions or symptoms of discase(s) or disorder(s) being treated. With respect to orlislat, the effective dose-is in the range ol about 50 to about 1440 mg/day given in one or more doses, preferably three limes daily, preferably in the range of about 120 to about 720 mg/da\ and more preferably in the range of about 120 to about 360 mg/day. Orlistat is preferably administered orally. With respect to the llbrate, the effective dose is in the range of about 10 to about 3000 mg/day given in one or more doses. preferably in the range of about 50 to about 1200 mg/day. and more preferably in the range ol about 50 to about 300 mg/day. The skilled artisan will understand and appreciate lluil the effective dose of a given fibrate will vary with the potency of the librale.
I he present invention relates to the unexpected discovery that co-administration of a llbrate and orlistat exerts benelleial cl'tccts in overweight or obese subjects, i.e. subjects having a BMI > 28 kg/m .
The llhrale may be selected from the group consisting of gemllbro/il, fenofibrale. be/allbrate. clollbratc and ciprollbrate: fenofibrate being the preferred II bra ic
I he cileetive dose ofthe llbrale is in the range of about It) to about 3000 ing per day and the effective dose of orlislal is in the range of about 50 to about I 440 nig per day.
According to the invention, the llbrate and orlislal can be administered simultaneously, or sequentially. In a preferred embodiment ofthe invention, the llbrate anil oilistat arc administered simultaneously, more preferably in one formulation containing the llbrate and orlistat.
Pharmaceutical formulations of the fibrate and/or orlistat molecules can be prepared according to known methods. 'J'he preferred route of administering the llbrate and orlistat is mucosal administration, most preferably oral administration.
for preparing pharmaceutical compositions containing a llbrate and/or orlistat, pharmaceutieally acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispcrsiblc granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
I he pharmaceutical composition ofthe invention comprising of a fibrate, orlislal and a pharmaceutieally acceptable carrier is found to show surprising therapeutic effects. Therefore the pharmaceutical composition is synergistic.
In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active eomponent(s). In tablets, the active coniponent(s) is (are) mixed \\iih the carrier having the necessary binding properties in suitable proportions and compacted in the shape and si/e desired. The powders and tablets
preferabK contain from live or ten to about seventy percent of the aelive component! s). Suitable carriers are magnesium carbonate, magnesium stearate. talc, sugar, ncctin. dextrin, starch, gelatin, tragacanth. metln Icellulose. sodium carbox\ mcllivlcellulosc. a low melting wax. cocoa butter, and the like.
I iqiiid lorm preparations include solutions, suspensions, and emulsions, lor example, water or water propylene glycol solutions. l;or parenteral injection liquid preparations can be formulated in solution e.g. in aqueous polyethylene glycol solution
Aqueous solutions suitable for oral use can be prepared b\ dissolving the active component in water and adding suitable colorants, flavors, slabili/ing and thickening agents as desired. Aqueous suspensions suitable for oral use can be made In dispersing the fine!) divided active component in water with viscous material, such as natural or synthetic gums, resins, metln Icellulose. sodium carboxs meld) Icellulose. and other well-known suspending agents.
\lsi> included are solid form preparations which are intended to be convened. shorth before use. to liquid form preparations for oral administration. Such liquid forms include solutions: suspensions, and emulsions. I hese preparations ma\ contain, in addition to the active component, colorants, flavors, slahili/ers. buffers, artificial and natural sweeteners, dispersants. thickeners, solubiii/ing agents, and the like.
I he pharmaceutical preparation 's preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active coniponent(s). I'he unit dosage form can be a packaged preparation, the package containing discrete quantities ol'the preparation, such as packeled tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lo/engc itself, or it can be the appropriate number of an\ ol these in packaged form.
I he amount ol each compound to be administered will depend on a number of (actors including the age of the patient, the severity ol the condition and the past medical history ol'the patient. It is generally envisaged that each unit dose contains I I ) from about 10 to about 1000 mg, preferably about 50 to 600 mg. more preferably about 50 to about 200 mg ol' flbrate. and/or from about 50 to
about 720 ing, preferably about 120 to about 360 mg of orlislal. Typical unit doses contain 67 mg. 140 mg, 160 mg, 200 mg, 500 mg or 600 mg of fibrate and/or 120 mg of orlistal.
The invention is further illustrated by the following example, which is not to be construed as limiting, but merely as an illustration of some preferred features of the invention.
EXAMPLE: Effect of a fibrate and orlistat co-administration on body weight
This study was designed to evaluate the effects of using a combination of fenofibrate and orlistal on body weight.
The data from this study, which are summari/ed in Table I. demonstrate that alter 6 weeks of treatment (I) there is a significant difference between mice with a high-fat diet, treated with fenofibratc alone or with orlistat alone, and mice with a standard diet (no normali/ation of the body weight is observed in treated mice), and (2) there is no difference between mice with a high-fat diet, treated with a combination of fenofibrate and orlistat, and mice with a standard diet (the body weight of the treated mice is normalized).
Therefore, better control of the body weight is obtained when orlistat is administered in combination with a fibrate. METHOD Animals:
Mice weighing approximately 20 g were received from CERJ. They were put into individual cages in a temperature-, humidity- and light- controlled room (2I-2.VJ(\ 12-l2h light-dark cycle). They were fed with either a standard laboratory diet or a high-fat diet, and had free access to water. After acclimatization, they were randomi/.ed into groups of 20 animals, based on body weight. The experimental groups were:
• (iroup I: mice fed with high-fat diet
• (iroup 2: mice fed with high-fat diet, treated with fenofibrate 25 mg/kg p.o.,
mixed with the diet
• Group 3: mice fed with high-fat diet, treated with orlistal 2.5 mg/kg p.o.,
mixed with the diet
• Group 4: mice fed with high-fat diet, treated with fenollhrate 25 mg/kg p.o.
and orlistat 2.5 mg/kg p.o.. mixed with the diet
• Group 5: mice led with standard diet
StciliMits : All data are presented as mean I sem. Results were subjected to Dunnetfs I test . A p - 0.05 was considered significant.

WE CLAIM:
1. A pharmaceutical composition for the treatment of obesity, said composition
containing fenofibrate, orlistat and pharmaceutically acceptable carrier(s), wherein the
weight ratio of fenofibrate to orlistat is in the range of 12.2 : 87.8 to 62.5 : 37.5.
2. A composition as claimed in 1, wherein the composition is in form of a solid or a
liquid.
3. A composition as claimed in claim 2, wherein the solid form includes powders,
tablets, pills, capsules, cachets, suppositories and dispersible granules.
4. A composition as claimed in claim 3, wherein in the powder and tablet form contain 5
to 70% of the active components.
5. A composition as claimed in claims 1 and 3, wherein the carriers for solid form are
selected from the group comprising magnesium carbonate, magnesium stearate, talc,
sugar, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium
carboxymethylcellulose, a low melting wax, cocoa butter and the like.
6. A composition as claimed in claim in 2, wherein the liquid form includes solutions,
suspensions, emulsions such as water propylene glycol solutions, and aqueous
suspensions such as aqueous polyethylene glycol solution.
7. A composition as claimed in claims 1 and 6, wherein the carriers for liquid form are
natural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose.
8. A composition substantially such as herein described and illustrated in the
accompanying specification.